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IKK mediates ischemia-induced neuronal death

Nature Medicine volume 11, pages 1322–1329 (2005)Cite this article

Abstract

The IκB kinase complex IKK is a central component of the signaling cascade that controls NF-κB–dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.

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Figure 1: Cerebral ischemia activates IKK in neurons.
Figure 2: Deficiency of IKK2 in neurons reduces ischemic brain damage.
Figure 3: Inhibition of IKK in neurons protects against ischemic damage.
Figure 4: Constitutive activation of IKK2 in neurons enhances ischemic damage.
Figure 5: The IKK inhibitor BMS-345541 ameliorates ischemic brain damage.
Figure 6: Inhibition of IKK reduces the expression of genes involved in eicosanoid biosynthesis.

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Acknowledgements

This study was supported by Deutsche Forschungsgemeinschaft grants SCHW 416/4-2 (to M.S.) and SFB 497/B1 (to B.B.), Bundesministerium für Bildung und Forschung grant NGFN2 (to M.S.), and European Union grant QLG1-CT-1999-00202 (to M.P.). We thank H. Schröck (Heidelberg) for help with physiological parameters, R. Kühn (Neuherberg, Germany) for providing CamKII-Cre mice, R. Klein (Munich) for providing Nestin-Cre mice and Y. Qiu (Bristol-Myers Squibb) for his work toward synthesis of BMS-345541.

Author information

Author notes

  1. Wen Zhang

    Present address: Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

  2. Oliver Herrmann, Bernd Baumann and Rossana de Lorenzi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg, 69120, Germany

    Oliver Herrmann, Sajjad Muhammad, Wen Zhang, Jens Kleesiek, Martin Köhrmann, Ioana Potrovita, Ira Maegele & Markus Schwaninger

  2. Department of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, Ulm, 89081, Germany

    Bernd Baumann, Max Malfertheiner & Thomas Wirth

  3. Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, Monterotondo, I-00016, Italy

    Rossana de Lorenzi & Manolis Pasparakis

  4. Institute of Neuroanatomy, Medical Clinic RWTH Aachen, Wendlingweg 2, Aachen, 52075, Germany

    Cordian Beyer

  5. Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Route 206 & Provinceline Road, Princeton, 08543, New Jersey, USA

    James R Burke

  6. Department of Biomedical Optics, Max-Planck Institute for Medical Research, Jahnstr. 29, Heidelberg, 69120, Germany

    Mazahir T Hasan

  7. ZMBH, University of Heidelberg, Im Neuenheimer Feld 282, Heidelberg, 69120, Germany

    Hermann Bujard

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Correspondence to Markus Schwaninger.

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Competing interests

James R. Burke is employed by Bristol-Meyers Squibb. Bristol-Meyers Squibb is interested in the development and commercialization of IKK2 inhibitors as therapeutics for the treatment of stroke.

Supplementary information

Supplementary Fig. 1

Nissl staining of coronal brain sections showed no gross anatomical differences between IKK2nKO and control mice. (PDF 203 kb)

Supplementary Fig. 2

Immunohistochemistry of IKK1/2 in sagittal brain slices of IKK2nDN animals. (PDF 277 kb)

Supplementary Fig. 3

Luciferase activity was measured in brain regions identical to Figure 3c. (PDF 78 kb)

Supplementary Fig. 4

Junb expression in IKK2nCA mice and littermate controls was determined by semi-quantitative RT-PCR in brain regions identical to Figure 4. (PDF 54 kb)

Supplementary Fig. 5

Induction of the proapoptotic genes Fas and Myc and of the antiapoptotic genes Birc3, Bdnf, Epo and Csf3 by MCAO was not inhibited by BMS-345541 treatment. (PDF 80 kb)

Supplementary Table 1

Physiological parameters of IKK2CNSKO mice and control mice. (PDF 23 kb)

Supplementary Table 2

Physiological parameteres of C57Bl/6 mice 20 min after intracerebroventricular injection of 2 μl saline or 20 mM BMS-345541 and 15 min after MCAO. (PDF 19 kb)

Supplementary Methods (PDF 34 kb)

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Herrmann, O., Baumann, B., de Lorenzi, R. et al. IKK mediates ischemia-induced neuronal death. Nat Med 11, 1322–1329 (2005). https://doi.org/10.1038/nm1323

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